Neil Osterweil

March 13, 2015

HOLLYWOOD, Florida — Give it 3 months, but if a patient with chronic myelogenous leukemia (CML) has a suboptimal response to therapy with a first-line tyrosine kinase inhibitor (TKI), it's not too soon to consider trying a different drug, according to clinical guidelines from the National Comprehensive Cancer Network (NCCN).

"It's hard for me to imagine how someone who has a lousy response at 3 months is suddenly going to molecularly turn the corner and be a great responder in another 3 months," said guideline codeveloper Jerald P. Radich, MD, from the Fred Hutchinson Cancer Research Center, in Seattle, Washington.

But the clinician should also keep in mind that what looks like failure of a targeted therapy for CML may actually be due to the patient's failure to take the drug, said Dr Radich here at the National Comprehensive Cancer Network (NCCN) 20th Annual Conference.

"I and other people have spent much taxpayer money trying to decide on whether you look at microbiology of the disease when [a CML patient] first comes in to predict response to therapy. We found nothing, nothing, nothing ― nothing that comes as close as getting people to take their drug," he said. "What we need to do is to have some test to tell whether people are actually adherent or not," he added.

NCCN guidelines for CML recommend evaluating patients 3 months after the start of therapy with a TKI, either imatinib (Gleevec, Novartis Pharmaceuticals Corporation), dasatinib (Sprycel, Bristol-Myers Squibb Company) or nilotinib (Tasigna, Novartis Pharmaceuticals Corporation). If at that time patients still have more than 10% of BCR-ABL1 transcripts or have not had a partial cytogenetic response on bone marrow cyotgenetics, the guidelines counsel evaluating patient compliance, looking for drug-drug interactions, and considering mutational analysis, with a treatment switch to a different primary TKI if warranted.

Noncompliance or poor compliance could well be the root of the problem, Dr Radich said. He noted that in the Adagio study (Blood. 2009;113:5401-5411), only 14.2% of patients who were prescribed imatinib for CML took the drug as prescribed, and 71% took less than their prescribed dose.

The reason all this matters comes from evidence that earlier molecular responses predict a higher probability of achieving a future major molecular response (MMR), which in turn is associated with longer duration of complete cytogenetic response and higher rates of both event-free survival and progression-free survival (PFS). In addition, patients who do not have an MMR or have one but later lose it have shorter PFS, he said.

He cited a 2011 study ( J Clin Oncol. 2012;3:232-8) showing that patients with less than 9.8% of BCR-ABL transcripts after 3 months of imatinib therapy had an 8-year survival of 93.3%, compared with 54% for patients with more than 9.8%.

In addition, a 2009 study ( Blood. 2009;114: Abstract 3290) showed that greater than 90% compliance with all prescribed imatinib doses was significantly associated with the chance of achieving an MMR (P < .0001).

Although there are no hard and fast rules (or hard data, for that matter) to say that changing therapy at 3 months is preferable to doing so at 6 months, testing at 3 months is important, because it allows clinicians to consider whether compliance, poor biology, or both may be at play, Dr Radich said.

Poor early response is a warning sign of progression, and if a bone marrow transplant is considered, the process of obtaining insurance approvals, HLA matching, and identifying suitable donors can take months and should be started as soon as possible, he added.

Why Wait?

Reasons for not waiting longer than 3 months to see a response include that "it's unlikely that the risk of changing drugs is greater than the benefit. We use all of these drugs in first-line therapy, and they're very safe, so it's unlikely that you're going to have problems if you're giving them another drug," Dr Radich said.

Additionally, he said, data from the IRIS (International Study of Interferon and ST1571) trial, which looked at responses to therapy at 6 months, may have led some investigators down the garden path toward the idea that it's okay to wait that long before deciding on a different drug.

But the problem with a landmark analysis such as the one used in IRIS is that at 6 months, "you lose all the people who have failed therapy up to that point, and so you have enriched for a population who is doing better than the other population," he said.

Same Old Story

The clinicians' uncertainty about whether a poor response is a matter of CML biology, drug metabolism, or patient noncompliance is a familiar one, commented meeting attendee Thomas L. Goodmnan, MD, from Upstate Hematology Oncology, in Niskayuna, New York.

"Compliance is a problem in all of oncology all the time," he said in an interview with Medscape Medical News. "Patients decide on their own that they're not going to take the drug, take only half the drug, take it every other day, or they decide, 'I'm going to hold off until I talk to the doctor when I see him in a month,' so that they have been off the drug for a month. And also, patients don't like to tell you the truth."

Dr Goodman said that in general, he follows the guideline recommendations and is willing to make a drug switch or, in the case of older, more frail patients, consider using a smaller dose that could lessen the likelihood of side effects that might cause patients to stop complying with therapy.

Dr Goodman was not involved in the development of the CML guidelines.

Dr Radich has reported serving as a scientific advisor to ARIAD Pharmaceuticals, Incyte Corporation, and Novartis Pharmaceuticals and receiving grant support and honoraria from Novartis. Dr Goodman has reported no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 12, 2015.

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